pan-Canadian Oncology Drug Review Final Economic Guidance Report Apalutamide (Erleada) for Castration-Resistant Prostate Cancer November 1, 2018

pCODR Final Economic Guidance Report - Apalutamide (Erleada) for Castration-Resistant Prostate Cancer pERC Meeting: August 16, 2018; pERC Reconsideration Meeting: October 18, 2018 © 2018 pCODR | PAN-CANADIAN ONCOLOGY DRUG REVIEW ii

DISCLAIMER Not a Substitute for Professional Advice This report is primarily intended to help Canadian health systems leaders and policymakers make well-informed decisions and thereby improve the quality of health care services. While patients and others may use this report, they are made available for informational and educational purposes only. This report should not be used as a substitute for the application of clinical judgment in respect of the care of a particular patient or other professional judgment in any decision making process, or as a substitute for professional medical advice. Liability pCODR does not assume any legal liability or responsibility for the accuracy, completeness or usefulness of any information, drugs, therapies, treatments, products, processes, or services disclosed. The information is provided "as is" and you are urged to verify it for yourself and consult with medical experts before you rely on it. You shall not hold pCODR responsible for how you use any information provided in this report. Reports generated by pCODR are composed of interpretation, analysis, and opinion on the basis of information provided by pharmaceutical manufacturers, tumour groups, and other sources. pCODR is not responsible for the use of such interpretation, analysis, and opinion. Pursuant to the foundational documents of pCODR, any findings provided by pCODR are not binding on any organizations, including funding bodies. pCODR hereby disclaims any and all liability for the use of any reports generated by pCODR (for greater certainty, "use" includes but is not limited to a decision by a funding body or other organization to follow or ignore any interpretation, analysis, or opinion provided in a pCODR report).

FUNDING The pan-Canadian Oncology Drug Review is funded collectively by the provinces and territories, with the exception of Quebec, which does not participate in pCODR at this time.

pCODR Final Economic Guidance Report - Apalutamide (Erleada) for Castration-Resistant Prostate Cancer pERC Meeting: August 16, 2018; pERC Reconsideration Meeting: October 18, 2018 © 2018 pCODR | PAN-CANADIAN ONCOLOGY DRUG REVIEW iii

INQUIRIES Inquiries and correspondence about the pan-Canadian Oncology Drug Review (pCODR) should be directed to: pan-Canadian Oncology Drug Review 154 University Avenue, Suite 300 Toronto, ON M5H 3Y9 Telephone: 613-226-2553 Toll Free: 1-866-988-1444 Fax: 1-866-662-1778 Email: info@pcodr.ca Website: www.cadth.ca/pcodr

pCODR Final Economic Guidance Report - Apalutamide (Erleada) for Castration-Resistant Prostate Cancer pERC Meeting: August 16, 2018; pERC Reconsideration Meeting: October 18, 2018 © 2018 pCODR | PAN-CANADIAN ONCOLOGY DRUG REVIEW iv

TABLE OF CONTENTS

DISCLAIMER ............................................................................................................... ii FUNDING .................................................................................................................. ii INQUIRIES ................................................................................................................. iii TABLE OF CONTENTS ................................................................................................... iii 1 ECONOMIC GUIDANCE IN BRIEF ............................................................................... 1

1.1 Submitted Economic Evaluation .......................................................................... 1 1.2 Clinical Considerations ..................................................................................... 2 1.3 Submitted and EGP Reanalysis Estimates ............................................................... 3 1.4 Detailed Highlights of the EGP Reanalysis .............................................................. 4 1.5 Evaluation of Submitted Budget Impact Analysis ...................................................... 6 1.6 Conclusions ................................................................................................... 7

2 DETAILED TECHNICAL REPORT ............................................................................... 8 This section outlines the technical details of the pCODR Economic Guidance Panel’s evaluation of the economic evidence that is summarized in Section 1. Pursuant to the pCODR Disclosure of Information Guidelines, this section is not eligible for disclosure. It was provided to the pCODR Expert Review Committee (pERC) for their deliberations.

3 ABOUT THIS DOCUMENT ....................................................................................... 9 REFERENCES ............................................................................................................. 10

pCODR Final Economic Guidance Report - Apalutamide (Erleada) for Castration-Resistant Prostate Cancer pERC Meeting: August 16, 2018; pERC Reconsideration Meeting: October 18, 2018 © 2018 pCODR | PAN-CANADIAN ONCOLOGY DRUG REVIEW 1

1 ECONOMIC GUIDANCE IN BRIEF

1.1 Submitted Economic Evaluation

The economic analysis submitted to pCODR by Janssen Inc. compared apalutamide in combination with androgen deprivation therapy (ADT) with ADT monotherapy for patients with non-metastatic castrate-resistant prostate cancer (nm-CRPC). The economic model only accounts for nm-CRPC patients who are at high risk for the development of metastases, which is defined as a prostate-specific antigen (PSA) doubling time of 10 months or less during continuous ADT according to the SPARTAN1 trial eligibility criteria, while the pCODR requested reimbursement indication is for broader population.

Table 1. Submitted Economic Model

Funding Request/Patient Population Modelled

Funding request: Patients with nm-CRPC. Patient Population Modelled: Consistent with SPARTAN1 study population: Adult men who have confirmed adenocarcinoma of the prostrate that is castration-resistant (no detectable distant metastases by either CT scan, MRI or technetium-99m bone scan) and are at high risk for the development of metastases; high risk defined as a PSA doubling time of 10 months or less during continuous ADT.

Type of Analysis CUA & CEA Type of Model Partitioned-survival Comparator Androgen deprivation therapy Year of costs 2018 Time Horizon 15 years Perspective Government Cost of apalutamide*

Apalutamide costs: • $28.34 per 60 mg tablet

At the recommended dose of 240 mg (four 60 mg tablets) administered orally once daily, apalutamide costs:

• $113.38 per day • $3,174.53 per 28-day cycle

Cost of leuprolide* Leuprolide costs: • $39.60 per mg

At the recommended dose of a 22.5 mg subcutaneous depot injection once every 3 months, leuprolide costs:

• $10.60 per day • $297.00 per 28-day cycle

Cost of bicalutamide* Bicalutamide costs: • $1.27 per 50 mg tablet

At the recommended dose of 50 mg once daily, bicalutamide costs:

• $1.27 per day

pCODR Final Economic Guidance Report - Apalutamide (Erleada) for Castration-Resistant Prostate Cancer pERC Meeting: August 16, 2018; pERC Reconsideration Meeting: October 18, 2018 © 2018 pCODR | PAN-CANADIAN ONCOLOGY DRUG REVIEW 2

• $35.56 per 28-day cycle Cost of goserelin* Goserelin costs:

• $111.55 per mg At the recommended dose of one depo injection 10.8 mg administered once every 13 weeks, goserelin costs:

• $13.29 per day • $370.69 per 28-day cycle

Cost of degarelix* Degarelix costs: • $3.19 per mg

At the recommended dose of one depo injection 80 mg per months, degarelix costs:

• $9.12 per day • $255.00 per 28-day cycle

Model Structure The model was comprised of 3 health states: metastasis-free survival, metastatic castrate resistant prostate cancer and death. These events were assumed to be progressive, mutually exclusive and irreversible. Patients enter the model in metastasis-free survival state and upon detection of metastases, transition to the metastatic state.

Key Data Sources SPARTAN1 phase III RCT * Drug costs for all comparators in this table are based on costing information under license from IMS Health Canada Inc. concerning the following information service(s): DeltaPA, and may be different from those used by the submitter in the economic model. The analyses, conclusions, opinions and statements expressed are those of the Canadian Agency for Drugs and Technologies in Health and not those of IMS Health Canada Inc. Quintile IMS DeltaPA – accessed on April, 2018. All calculations are based on 70kg and BSA = 1.7m2

1.2 Clinical Considerations

According to the pCODR Clinical Guidance Panel (CGP), this comparison is appropriate as there is no defined and generally accepted or approved standard therapy for patients with high risk nm-CRPC. • Relevant issues identified included:

o There is a net overall clinical benefit to apalutamide in combination with ADT compared to ADT alone for this patient population.

o The SPARTAN trial demonstrated statistically significant and clinically meaningful benefit in metastasis-free survival (primary end point) for apalutamide plus ADT. Overall survival is currently immature.

o Apalutamide is well tolerated, with few clinically relevant grade 3 and grade 4 side effects.

o There are currently no treatment options for patients with non-metastatic castration resistant prostate cancer.

• Generalizability issues include: o The trial limited inclusion to patients with ECOG performance status of 0 and 1. o The trial included only high risk patients.

pCODR Final Economic Guidance Report - Apalutamide (Erleada) for Castration-Resistant Prostate Cancer pERC Meeting: August 16, 2018; pERC Reconsideration Meeting: October 18, 2018 © 2018 pCODR | PAN-CANADIAN ONCOLOGY DRUG REVIEW 5

and (iii) adherence to therapies in the metastatic renal cell carcinoma setting. The submitter noted that the published literature provided, suggests that: (i) the compliance results for apalutamide plus ADT observed in the controlled setting of the SPARTAN trial are higher than adherence to oral anticancer medications observed in real-world settings, and (ii) adherence to ADT is higher than the adherence to oral anticancer agents for treatment of prostate and other cancers. Consequently, the submitter did not agree with the EGP’s assumption of equal treatment compliance between apalutamide plus ADT and ADT treatment arms, but proposed to keep the submitter’s original input in the model, which assumed the compliance rates from the SPARTAN trial for the non-metastatic setting. The EGP maintains its choice of setting treatment compliance equally for both treatment arms (apalutamide plus ADT and ADT) in the economic model at 94.83% for the following reason:

o The CGP felt that: apalutamide is well tolerated and there is no clinical reason for low compliance. from a clinician point of view, clinicians always strive for the highest dose

intensity possible and educate their patients accordingly. Therefore, it is reasonable to assume a conservative scenario in which patients actually take their medications (apalutamide and ADT) as prescribed.

one could argue that the compliance rate for intravenous drugs could be lower, too, as in clinical practice cycles are commonly being delayed or skipped.

• Parametric curve time to treatment discontinuation: The submitter wished to fit the same parametric curve for both the treatments for treatment discontinuation. As there was no curve that ideally fit both treatments, in the submitted base case they selected the Weibull curve, the 3rd best for apalutamide plus ADT and 4th best for placebo plus ADT. The EGP examined the gamma curve, which was tied for 3rd best fit with the Weibull curve for apalutamide plus ADT and was the second best fit for placebo plus ADT.

pCODR Final Economic Guidance Report - Apalutamide (Erleada) for Castration-Resistant Prostate Cancer pERC Meeting: August 16, 2018; pERC Reconsideration Meeting: October 18, 2018 © 2018 pCODR | PAN-CANADIAN ONCOLOGY DRUG REVIEW 7

and specificity of such a diagnostic test is not quantified and the impact on the number of patients is unknown.

1.6 Conclusions

The EGP’s best estimate of ∆C and ∆E for apalutamide in combination with ADT when compared to ADT monotherapy is: • $198,826/QALY • The extra cost of apalutamide plus ADT is $113,035 (ΔC). The main factors that influence

ΔC are the time to treatment discontinuation curve and the duration of treatment effect. • The extra clinical effect of apalutamide plus ADT is 0.57 (ΔE). The main factors that

influence ΔE are the duration of treatment effect, the time horizon and the source of utilities.

Overall conclusions of the submitted model: • There is uncertainty in the model structure as evidenced by the variability in the ICER,

despite running 10,000 simulations. • There is a large variability in the incremental QALYs. • The EGP was unable to address all the limitations noted above through scenario analyses.

pCODR Final Economic Guidance Report - Apalutamide (Erleada) for Castration-Resistant Prostate Cancer pERC Meeting: August 16, 2018; pERC Reconsideration Meeting: October 18, 2018 © 2018 pCODR | PAN-CANADIAN ONCOLOGY DRUG REVIEW 8

2 DETAILED TECHNICAL REPORT This section outlines the technical details of the pCODR Economic Guidance Panel’s evaluation of the economic evidence that is summarized in Section 1. Pursuant to the pCODR Disclosure of Information Guidelines, this section is not eligible for disclosure. It was provided to the pCODR Expert Review Committee (pERC) for their deliberations.

pCODR Final Economic Guidance Report - Apalutamide (Erleada) for Castration-Resistant Prostate Cancer pERC Meeting: August 16, 2018; pERC Reconsideration Meeting: October 18, 2018 © 2018 pCODR | PAN-CANADIAN ONCOLOGY DRUG REVIEW 9

3 ABOUT THIS DOCUMENT

This Economic Guidance Report was prepared by the pCODR Economic Guidance Panel and supported by the pCODR Genitourinary Clinical Guidance Panel and the pCODR Methods Team. This document is intended to advise the pCODR Expert Review Committee (pERC) regarding resource implications and the cost-effectiveness of apalutamide (Erleada) for non-metastatic castration-resistant prostate cancer. A full assessment of the clinical evidence of [drug name and indication] is beyond the scope of this report and is addressed by the relevant pCODR Clinical Guidance Report. Details of the pCODR review process can be found on the pCODR website (www.cadth.ca/pcodr).

pCODR considers it essential that pERC recommendations be based on information that can be publicly disclosed. Information included in the Economic Guidance Report was handled in accordance with the pCODR Disclosure of Information Guidelines. There was no non-disclosable information in the Economic Guidance Report provided to pERC for their deliberations.

This Final Economic Guidance Report is publicly posted at the same time that a pERC Final Recommendation is issued. The Final Economic Guidance Report supersedes the Initial Economic Guidance Report. Note that no revisions were made in between posting of the Initial and Final Guidance Reports.

The Economic Guidance Panel is comprised of economists selected from a pool of panel members established by the pCODR Secretariat. The panel members were selected by the pCODR secretariat, as outlined in the pCODR Nomination/Application Information Package and the Economic Guidance Panel Terms of Reference, which are available on the pCODR website (www.cadth.ca/pcodr). Final selection of the pool of Economic Guidance Panel members was made by the pERC Chair in consultation with the pCODR Executive Director. The Economic Guidance Panel is editorially independent of the provincial and territorial Ministries of Health and the provincial cancer agencies.

pCODR Final Economic Guidance Report - Apalutamide (Erleada) for Castration-Resistant Prostate Cancer pERC Meeting: August 16, 2018; pERC Reconsideration Meeting: October 18, 2018 © 2018 pCODR | PAN-CANADIAN ONCOLOGY DRUG REVIEW 10

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